Biol. Pharm. Bull. 28(8) 1531—1534 (2005)

creasing providing a rapidly expanding market for antiallergic drugs. The first generation anti-histamines penetrate the blood brain barrier and also possess anticholinergic properties and this has led to the development of a second generation of H1-antagonists such as terfenadine and astemizole. A common feature of first generation compounds includes two aryl or heteroaryl rings linked to an aliphatic tertiary amine via the side chain (e.g. Diphenhydramine and Pheniramine), the second generation compounds (terfenadine and cetirizine) also contain many of the structural features of first generation compounds. The real breakthrough of non-sedative antihistamines came in the early eighties of twentieth century when the discovery of modern antihistamines, was found to exhibit potent antihistaminic activity without sleepinducing effect. Condensed heterocycles containing new generation of H1-antihistamines (e.g. Loratadine, Azelastine and Flazelastine) that does not possessing the above mentioned pharmacophore for H1-antihistamines gave way for the discovery of many novel antihistamines (temelastine and mangostin). A literature survey reveals excellent antihistaminic activity in quinazolines and condensed quinazolines. In view of these facts and to continue our efforts in the search of quinazolines derived potent antihistamines with least sedation, we aimed to synthesize a series of 1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones containing 3methylphenyl substitution at position 4 and alkyl substitution at position 1. The title compounds were synthesized by the cyclization of 2-hydrazino-3-(3-methylphenyl)quinazolin4(3H)-one (6) with various one carbon donors. The 2-hydrazino-3-(3-methylphenyl)quinazolin-4(3H)-one (6), was synthesized from 3-methylaniline 1, by a novel route (Chart 1). Spectral data (IR, NMR and mass spectra) confirmed the structures of the synthesized compounds, the purity of these compounds was ascertained by microanalysis (Table 1). The synthesized compounds were tested for their in vivo H1-antihistaminic activity on conscious guinea pigs. As sedation is one of the major side effects associated with antihistamines, the test compounds were also evaluated for their sedative potentials, by measuring the reduction in loco motor activity using actophotometer.